There are 39.6 million individuals aged 65 years or older in the US, a number expected to increase to approximately 72 million by 2030. Reduced immune function in the elderly is a major cause of morbidity, lower quality of life and death. Intriguingly, aging of thymus precedes aging of other organs and is a central feature and precursor of weak immune vigilance that appears in later life. Diminished ability of the thymus to produce naive T cells with progressive aging remains a puzzling phenomenon in Aging Research and to date, an intractable clinical condition that contributes to immune dysfunction in the elderly. This project will allow us to assess specific hypotheses and predictions about the relationship between age-related thymic demise and the role of 'thymic inflammaging' - in particular, the mechanism of inflammosome activation that causes thymic damage - with implications for understanding clinically relevant basic pathways to strengthen the immune system in the elderly. The current proposal is based on our discovery that aging of thymus can be substantially delayed by lowering the intrathymic caspase-1 activation via an Nlrp3 inflammasome dependent mechanism 7. The Nlrp3 (for nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome is formed via protein-protein interactions between Nlrp3, Asc and pro-caspase-1 proteins. The Nlrp3 inflammasome senses microbial byproducts as well as damage-associated molecular patterns (DAMPs) and upon assembly, causes caspase-1 activation, which in turn controls the secretion of pro-inflammatory cytokines IL-1b and IL-18. We identified that ceramides (lipids with sphingosine linked to a fatty acid) which increase in aging thymus, trigger the activation of Nlrp3 inflammasome. Ablation of Nlrp3 inflammasome in mice protects from thymic demise suggesting delayed immunological aging. Based on our novel findings, the central hypothesis of this proposal is that age-related thymic lipotoxicity via a canonical Nlrp3 Inflammasome dependent mechanism induces 'thymic inflammaging' and compromises thymic lymphopoiesis by impacting the integrity of thymic epithelial cells. The overall goal of this project is to identify basic mechanism of thymic demise that are amenable for future clinical intervention to delay or even reverse thymic involution in middle-aged or elderly people.